Our previous competing application of the Program Project Grant (PPG), entitled, "Signal Transduction and Alzheimer's Disease", was reviewed in October 2006 and the grant awarded for 5 years from 02/07 to 01/12. This supplemental application grew out of new studies that were related to part of Project 1 of that application (entitled "Effects of Ap on Synaptic Structure, Transmission and Plasticity1). Project 1 has focused on the very early stages of synapse loss associated with the actions of the (-amyloid peptide (A(), a causative factor in Alzheimer's disease (AD). In particular, our studies in Project 1 suggest that A( may negatively influence synaptic structure and function by virtue of its effects on the actin cytoskeleton. In new studies that represent a significant extension of Project 1, we have found that regulation of the actin cytoskeleton by A( appears to be linked to synaptic pathology including spine loss, and deficits in plasticity, through modulation of mitochondrial function. In this Supplement, we propose to examine the molecular details of the regulation of mitochondrial function by A(. In Specific Aim 1, we will investigate the dynamics of the actin cytoskeleton, and its role in mitochondrial motility, fission and translocation to dendritic spines, both under control conditions and in response to the actions of A(. In Specific Aim 2, we will investigate the role of WAVE1 and its phosphorylation in A(- and neuronal activity-regulated mitochondrial fission and translocation to spines. We will also investigate the role of cAMP and NO/cGMP signaling pathways in mitochondrial fission, motility and translocation and how this is influenced by A(. In Specific Aim 3, we will characterize the mechanisms involved in mitochondrial localization of WAVE1. We will investigate the role of proteins in the WAVE1 complex as well as of other proteins that interact with mitochondria in mediating the interaction between WAVE1 and mitochondria. The new studies carried out in this Supplement will complement continuing work being carried out in Project 1 and the other two projects. Together, this work will elucidate fundamental molecular mechanisms involved in the effects of A( on synaptic pathology and will provide potential new targets for AD therapies.